The main objective of this research proposal is to study the molecular mechanisms of central dopamine receptor functions in an animal model for dopaminergic supersensitivity. Dopamine receptor subtypes in the brain have been classifed based on the results from radioligand binding studies. D1 receptors are coupled with the adenylate cyclase system while the mechanism for D2 receptors has not been clearly defined. The receptor binding studies have revealed that the clincial functions of central dopamine system are associated more with the D2 receptors than the D1 receptor-linked adenylate cyclase. Chronic treatment of rats with the neuroleptic drug, haloperidol, has previously been shown to increase calcium-calmodulin (Ca-CaM)-dependent striatal membrane phosphorylation, which may ultimately govern the dopaminergic activity at the post-synaptic receptors. These findings appear to be consistent with the increased D2 receptor binding sites and the potentiated dopamine receptor sensitivity as observed by other workers using the same animal model. It is therefore important, as described in this proposal, to investigate the intimate role of Ca-CaM system in modulating the dopamine receptor sensitivity and also to determine the subtype of dopamine receptors it modulates. These goals will be carried out by simultaneously studying the chronic effects of neuroleptic drugs on the stereotyped behavior, the dopamine receptor binding sites and the Ca-CaM-dependent protein phosphorylation. Several neuroleptic drugs which are known to elicit selective pharmacological actions on the dopamine receptor subtypes are chosen to be used in this study. At the beginning of this investigation, I intend to complete establishing the in vitro dopamine receptor binding assay n this laboratory. The actions of Ca-CaM-dependent protein kinase on striatal protein phosphorylation will be further characterized by distinguishing the role of this kinase from other possible participating enzymes such as the calcium-phospholipid-dependent protein kinase and the phosphoprotein phosphatase. Other long term prospects of this research and the overall hypothesis to be tested are also presented in this application.